Repeated exposure to cocaine and other psychostimulants produces long-term behavioral changes in both man (craving, paranoid ideation, hallucinations and endocrine changes) and the experimental animal (operant behaviors, sensitization, cognitive impairment and discriminative conditioning). In view of the alarming dimensions of cocaine abuse, there is a need for a better understanding of the mechanism(s) underlying these long-term effects. Since many of the immediate and long-term behavioral effects of cocaine involve central dopamine (DA), assessing DA neuronal function during cocaine withdrawal may provide a useful approach to this question. Long-term changes in DA neuronal function can be assessed from the changes in DA release and metabolism. These parameters can be evaluated in the rat brain from the steady-state concentrations and/or rates of formation measurements of 3-methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC). Most studies on cocaine short- and long-term effects come from acute experiments; the striatum and nucleus accumbens were the regions most frequently analyzed. We have previously reported selective long-term reductions in DOPAC concentrations in the frontal cortex and hypothalamus in rats during cocaine withdrawal, suggesting a reduction in dopamine turnover in these regions. But since 3MT and DOPAC rates of production are believed to better reflect DA release and metabolism than steady-state concentrations, we have concentrated our efforts in the last 18 months on evaluating the effects of cocaine withdrawal on the production dynamics of these metabolites in four important brain regions (frontal cortex, hypothalamus, nucleus accumbens and striatum).